A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma.
Chemotherapy induces apoptosis and tumor regression primarily through activation of p53-mediated transcription. Neuroblastoma is a p53 wild type malignancy at diagnosis and repression of p53 signaling plays an important role in its pathogenesis. Recently developed small molecule inhibitors of the MD...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3865347?pdf=render |
| _version_ | 1828789348677451776 |
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| author | Eveline Barbieri Katleen De Preter Mario Capasso Peter Johansson Tsz-Kwong Man Zaowen Chen Paris Stowers Gian Paolo Tonini Frank Speleman Jason M Shohet |
| author_facet | Eveline Barbieri Katleen De Preter Mario Capasso Peter Johansson Tsz-Kwong Man Zaowen Chen Paris Stowers Gian Paolo Tonini Frank Speleman Jason M Shohet |
| author_sort | Eveline Barbieri |
| collection | DOAJ |
| description | Chemotherapy induces apoptosis and tumor regression primarily through activation of p53-mediated transcription. Neuroblastoma is a p53 wild type malignancy at diagnosis and repression of p53 signaling plays an important role in its pathogenesis. Recently developed small molecule inhibitors of the MDM2-p53 interaction are able to overcome this repression and potently activate p53 dependent apoptosis in malignancies with intact p53 downstream signaling. We used the small molecule MDM2 inhibitor, Nutlin-3a, to determine the p53 drug response signature in neuroblastoma cells. In addition to p53 mediated apoptotic signatures, GSEA and pathway analysis identified a set of p53-repressed genes that were reciprocally over-expressed in neuroblastoma patients with the worst overall outcome in multiple clinical cohorts. Multifactorial regression analysis identified a subset of four genes (CHAF1A, RRM2, MCM3, and MCM6) whose expression together strongly predicted overall and event-free survival (p<0.0001). The expression of these four genes was then validated by quantitative PCR in a large independent clinical cohort. Our findings further support the concept that oncogene-driven transcriptional networks opposing p53 activation are essential for the aggressive behavior and poor response to therapy of high-risk neuroblastoma. |
| first_indexed | 2024-12-12T01:10:57Z |
| format | Article |
| id | doaj.art-1c189849586945f49531493917b116fb |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-12T01:10:57Z |
| publishDate | 2013-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-1c189849586945f49531493917b116fb2022-12-22T00:43:28ZengPublic Library of Science (PLoS)PLoS ONE1932-62032013-01-01811e7984310.1371/journal.pone.0079843A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma.Eveline BarbieriKatleen De PreterMario CapassoPeter JohanssonTsz-Kwong ManZaowen ChenParis StowersGian Paolo ToniniFrank SpelemanJason M ShohetChemotherapy induces apoptosis and tumor regression primarily through activation of p53-mediated transcription. Neuroblastoma is a p53 wild type malignancy at diagnosis and repression of p53 signaling plays an important role in its pathogenesis. Recently developed small molecule inhibitors of the MDM2-p53 interaction are able to overcome this repression and potently activate p53 dependent apoptosis in malignancies with intact p53 downstream signaling. We used the small molecule MDM2 inhibitor, Nutlin-3a, to determine the p53 drug response signature in neuroblastoma cells. In addition to p53 mediated apoptotic signatures, GSEA and pathway analysis identified a set of p53-repressed genes that were reciprocally over-expressed in neuroblastoma patients with the worst overall outcome in multiple clinical cohorts. Multifactorial regression analysis identified a subset of four genes (CHAF1A, RRM2, MCM3, and MCM6) whose expression together strongly predicted overall and event-free survival (p<0.0001). The expression of these four genes was then validated by quantitative PCR in a large independent clinical cohort. Our findings further support the concept that oncogene-driven transcriptional networks opposing p53 activation are essential for the aggressive behavior and poor response to therapy of high-risk neuroblastoma.http://europepmc.org/articles/PMC3865347?pdf=render |
| spellingShingle | Eveline Barbieri Katleen De Preter Mario Capasso Peter Johansson Tsz-Kwong Man Zaowen Chen Paris Stowers Gian Paolo Tonini Frank Speleman Jason M Shohet A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma. PLoS ONE |
| title | A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma. |
| title_full | A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma. |
| title_fullStr | A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma. |
| title_full_unstemmed | A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma. |
| title_short | A p53 drug response signature identifies prognostic genes in high-risk neuroblastoma. |
| title_sort | p53 drug response signature identifies prognostic genes in high risk neuroblastoma |
| url | http://europepmc.org/articles/PMC3865347?pdf=render |
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